Angelo Raffaele De Gaudio

Pharmacokinetic Evaluation of Meropenem and Imipenem in Critically Ill Patients with Sepsis

ObjectiveTo evaluate and compare the pharmacokinetic profiles of imipenem and meropenem in a population of critically ill patients with sepsis to find possible differences that may help in selecting the most appropriate drug and/or dosage in order to optimise empiric antimicrobial therapy.Patients and methodsThis was a single-centre, randomised, nonblind study of the pharmacokinetics of both intravenous imipenem 1g and meropenem 1g in 20 patients admitted to an intensive care unit with sepsis in whom antimicrobial therapy was indicated on clinical grounds. Patients were divided into two groups: group I received intravenous imipenem 1g plus cilastatin 1g, and group II received intravenous meropenem 1g over 30 minutes. Peripheral blood samples were collected at 0, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the first dose and were centrifuged for 10 minutes at 4°C. Urine samples were collected during the 8 hours after antimicrobial administration at 2-hour intervals: 0–2, 2–4, 4–6 and 6–8 hours. The total volume of urine was recorded; the serum and urine samples were immediately frozen and stored at −80°C until assayed. Pharmacokinetic analysis was carried out through computerised programs using the least-square regression method and a two-compartment open model. Statistical differences were evaluated by means of one-way ANOVA.ResultsThe following pharmacokinetic differences between the two drugs were observed: the imipenem mean peak serum concentration was significantly higher than for meropenem (90.1 ± 50.9 vs 46.6 ± 14.6 mg/L, p < 0.01); the area under the serum concentration-time curve was significantly higher for imipenem than for meropenem (216.5 ± 86.3 vs 99.5 ± 23.9 mg · h/L, p < 0.01), while the mean volume of distribution and mean total clearance were significantly higher for meropenem than for imipenem (25 ± 4.1 vs 17.4 ± 4.5L, p < 0.01 and 191 ± 52.2 vs 116.4 ± 42.3 mL/min, p < 0.01, respectively).ConclusionThe more favourable pharmacokinetic profile of imipenem compared with meropenem in critically ill patients with sepsis might balance the possibly greater potency demonstrated in vitro for meropenem against Gram-negative strains. Hence, the clinical efficacy of the two carbapenems depends mostly on their correct dosage.

A multidrug-resistant Acinetobacter baumannii outbreak in intensive care unit: antimicrobial and organizational strategies.

PURPOSE Multidrug-resistant Acinetobacter baumannii (MRAB) is an emerging cause of intensive care unit (ICU) outbreaks. Patients are the main reservoirs, inducing cross transmission. We describe an MRAB outbreak that occurred in the Prato Hospital ICU in June to August 2009. MATERIALS AND METHODS The ICU consists of 2 separated 4-bed rooms (rooms A and B). The MRAB-positive patients were included in our study. During the outbreak, infection control measures were enhanced; patients and environmental screenings were performed. A 6-month follow-up was carried out. RESULTS Four of 26 patients admitted during the outbreak were MRAB positive. All patients were located in room A; no case was detected in room B either in the hospital or during the follow-up. Management included closure to new admissions, reinforcement of infection control measures, patient and environmental screenings, discharge of room B MRAB-negative patients for at least 5 days after the first case identification. All isolates were carbapenems resistant and tigecycline and colistin susceptible. All patients received tigecycline: 2 were successfully treated, 1 died because of preexisting illness, and 1 developed resistance and recovered after colistin therapy. CONCLUSIONS Enhanced infection control measures and adequate antibiotic strategy limited the outbreak. Tigecycline allowed rapid recovery. Nevertheless, resistance ensued; so colistin remained the only therapeutic option. However, pan-drug resistance has been reported.

Dynamic response of liquid-filled catheter systems for measurement of blood pressure: precision of measurements and reliability of the Pressure Recording Analytical Method with different disposable systems ☆

PURPOSE We aimed to compare the effects of a blood pressure transducer system specifically manufactured to limit underdamping artifacts with those of a standard system on hemodynamic parameter estimation and accuracy. MATERIALS AND METHODS Forty-three consecutive patients undergoing vascular surgery at the University of Florence, Italy, were included. Arterial blood pressure signal was simultaneously registered with 2 MostCare monitors, connected to the artery either by a standard transducer or a specific transducer manufactured to avoid underdamping artifacts (Resonance Over-Shoot Eliminator [R.O.S.E.]; Becton Dickinson, Becton Drive, NJ). Patients were divided into 2 groups: absence (C group) or presence (R group) of underdamping/resonance artifacts of blood pressure signal. Systolic blood pressure, cardiac index, maximal pressure/time ratio (dP/dt(MAX)), and cardiac cycle efficiency were recorded every 30 seconds for 30 minutes. A total of 2675 measurements were performed with 34.9% incidence of underdamping/resonance artifacts. RESULTS All hemodynamic parameters showed clinically acceptable differences in the C group; in contrast, the results differed greatly in the R group between standard and R.O.S.E. transducer (systolic blood pressure bias, 16.7 mm Hg; cardiac index bias, 0.24 L min(-1) m(-2); dP/dt(MAX) bias, 0.92 mm Hg/ms; cardiac cycle efficiency bias, 0.018 units). CONCLUSIONS Underdamping/resonance artifacts frequently affect blood pressure measurement in operating rooms and intensive care units and cause severe overestimation of systolic blood pressure and incorrect estimation of hemodynamic parameters when the pulse contour method is used.

Pre-emptive analgesia for postoperative pain control: a review.

Pain can play an important role at the social and psychological level; hence one of the major goals of anaesthesia is to control and reduce the incidence of postoperative pain. The use of an analgesia before surgical incision may offer one of the most innovative and promising strategies for better pain control throughout the perioperative period. Pre-emptive analgesia refers to pharmacological intervention initiated prior to a painful stimulus in order to inhibit nociceptive mechanisms before they are triggered. Pre-emptive analgesia has three objectives: to reduce pain resulting from the activation of inflammatory mechanisms triggered by surgical incision; to hinder the pain memory response of the central nervous system; and to ensure a good control of postoperative pain in order to avoid the development of chronic pain. The following provides an overview of the scientific rationale for pre-emptive analgesia alongside an overview of published systematic reviews and randomized clinical trials related to this topic.

Altered pharmacology in the intensive care unit patient

Critically ill patients, not infrequently present alterations of physiological parameters that determine the success/failure of therapeutic interventions as well as the final outcome. Sepsis and polytrauma are two of the most common and complex syndromes occurring in Intensive Care Unit (ICU) and affect drug absorption, disposition, metabolism and elimination. Pharmacological management of ICU patients requires consideration of the unique pharmacokinetics associated with these clinical conditions and the likely occurrence of drug interaction. Rational adjustment in drug choice and dosing contributes to the appropriateness of treatment of those patients.

Minocycline but not tigecycline is neuroprotective and reduces the neuroinflammatory response induced by the superimposition of sepsis upon traumatic brain injury.

Objective:The development of sepsis in patients with traumatic brain injury increases mortality, exacerbates morphological and functional cerebral damage, and causes persistent neuroinflammation, including microglial activation. The administration of antibiotics possessing both antimicrobial and immunomodulatory activity might attenuate both sepsis and posttraumatic cerebral inflammation. We compared the potential therapeutic efficacy of two tetracyclines, minocycline and the newer generation tigecycline, on functional neurobehavioral impairment and regional histopathological damage in an experimental model of combined traumatic brain injury and sepsis. Design:Prospective, experimental animal study. Setting:University Research Laboratory. Subjects:Adult male Sprague-Dawley rats. Interventions:Controlled cortical impact was used to induce traumatic brain injury and cecal ligation and puncture for sepsis. Immediately following injury, animals were treated with minocycline (45 mg/kg intraperitoneal), tigecycline (7.5 mg/kg intraperitoneal), or saline every 12 hours for 3 days. Measurements and Main Results:The development of sepsis and cerebral inflammatory response were evaluated, respectively, by 1) growth of peritoneal microorganisms and clinical variables and 2) tumor necrosis factor-&agr; expression in the perilesional cortex. To assess posttraumatic outcome, vestibulomotor and cognitive function were evaluated at different time points for 14 days post injury whereupon animals were killed and cerebral tissue analyzed for lesion volume, regional hippocampal (CA1/CA3) cell death, and microglial activation in the perilesional cortex, lesion core zone, and choroid plexus. Treatment with both antibiotics reduced microorganism growth, body weight loss, and mortality but had no effect on vestibulomotor or cognitive function. Minocycline alone attenuated postinjury cortical lesion volume, hippocampal CA3 neuronal cell loss, tumor necrosis factor-&agr; expression, and the extent of microglial activation and infiltration. Conclusions:The significantly heightened mortality caused by the superimposition of sepsis upon traumatic brain injury can be reduced by administration of both antibiotics but only minocycline can decrease the extent of cell death in selectively cortical and hippocampal brain regions, via, in part, a reduction in cerebral inflammation.

Infection prevention in the intensive care unit: Review of the recent literature on the management of invasive devices

Abstract Over the last 5 y, clinical trials investigating products, procedures, and treatments aimed at preventing infections in the intensive care unit have been described. The findings of these studies appear to confirm the effectiveness of certain preventive procedures. With regard to ventilator-associated pneumonia, the efficacies of decontamination of the oral cavity, continuous suction of subglottic secretions, positioning of the patient, selective decontamination of the digestive tract, and (for higher-risk patients) endotracheal tubes coated with silver, have been demonstrated. Medicated catheters and chlorhexidine-based dressings have been found useful for catheter-related bloodstream infections, and medical catheters have also been shown to be efficacious against urinary tract infections. All these procedures can be incorporated into departmental protocols for the prevention of nosocomial infections in the intensive care unit.

Is procalcitonin a reliable marker of sepsis in critically ill septic patients undergoing continuous veno-venous hemodiafiltration with “high cut-off” membranes (HCO-CVVHDF)?

*Corresponding author: Dr. Anna Caldini, General Laboratory, Clinical Chemistry Laboratory, Laboratory Diagnostics Department, Careggi University Hospital, Largo Brambilla, 3, 50134 Florence, Italy, Phone: +39 055-7949452, Fax: +39 055-7949416, E-mail: caldinia@aou-careggi.toscana.it Cosimo Chelazzi, Claudia Giannoni, Gianluca Villa and Angelo R. De Gaudio: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Florence, Italy Alessandro Terreni, Tiziana Biagioli and Gianni Messeri: Clinical Chemistry Laboratory, Laboratory Diagnostics Department, Careggi University Hospital, Florence Italy

Endovascular electrocardiography to guide placement of totally implantable central venous catheters in oncologic patients

Purpose Appropriate tip position of totally implantable central venous catheters is essential in order to prevent catheter-related complications, in particular thrombosis. Endovascular electrocardiography is an economic and safe method to guide placement of catheters into the central veins. Although widely utilized, there is still lack of conclusive evidence about its efficacy. The aim of the study was to assess the efficacy and safety of endovascular electrocardiographic guided placement compared to the anthropometric method. Methods Endovascular ECG was employed to guide electrocardiographic placement of a central venous catheter in a cohort of oncologic patients. The rate of correct placement and the incidence of catheter-related thrombosis were considered. Patients in which central venous catheters were inserted with the anthropometric technique were considered as control group. Results The rate of correct placement was 91% and 50% for ECG-guided and anthropometric catheters (p<0.0001) respectively. None of the patients suffered from early insertion-related complications. The rate of catheter-related vascular thrombosis was lower for ECG-guided catheters (3.6% vs. 9.6%, n.s.), in particular for left-inserted catheters (0% vs. 33.3%, p=0.02). Conclusion Endovascular electrocardiography was more effective than the anthropometric technique in placement of implantable central venous catheters and was associated with a lower incidence of catheter-related thrombosis, in particular for those inserted from the left-side.

Vasodilator activity of hydrogen sulfide (H2S) in human mesenteric arteries

The role of endogenous H2S has been highlighted as a gaseous transmitter. The vascular smooth muscle inhibitory effects of H2S have been characterized in isolated aorta and mesenteric arteries in rats and mice. Our study was aimed at investigating the vascular effects of H2S on human isolated mesenteric arteries and examining the underlying mechanisms involved. All experiments were performed on rings (4-8mm long) of human mesenteric arteries obtained from patients undergoing abdominal surgery. Ethical approval was obtained from the Ethics Committee of the University Hospital of the University of Florence (app. N. 2015/0024947). The effect of NaHS, an H2S donor, was determined using noradrenaline pre-contracted human isolated mesenteric rings. NaHS evoked a concentration-dependent relaxation (EC50 57μM). In contrast, homocysteine, an endogenous precursor of H2S, failed to affect human isolated mesenteric rings. Vasorelaxant response to NaHS was reduced by endothelium removal, application of the nitric oxide synthase inhibitor L-NAME and ODQ inhibitor of cyclic GMP. SQ 22536, an adenylate-cyclase inhibitor, failed to block NaHS-induced vasorelaxation. Inhibition of endogenous prostanoid production by indomethacin significantly reduced NaHS induced vasorelaxation. The role of potassium channels was also examined: blockers of the Ca2+-dependent potassium channel, charybdotoxin and apamin, failed to have any influence on the relaxant response to NaHS on this vascular tissue. In summary, H2S induced relaxation of isolated rings of human mesenteric arteries. Endothelium-dependent related mechanisms with the stimulation of ATP-sensitive potassium channels represents important cellular mechanisms for H2S effect on human mesenteric arteries.